N-0923 (rotigotine; S(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin) is a potent and selective dopamine D2 agonist playing a significant role in the treatment of all diseases associated with a dopamine-related metabolic disorder such as Parkinson's disease and Restless Leg. Various attempts have been made in the past at administering N-0923 in therapeutically meaningful quantities.
It was found, however, that due to a distinct first-pass effect the bioavailability after oral administration is merely about 0.5% (Swart and Zeeuw, Pharmazie 47 (1992) 613), ruling out oral administration of N-0923.
Moreover, even when the substance is parenterally administered in an aqueous solution, it is rapidly eliminated. The half-time value of N-0923 after intravenous injection in monkeys in an aqueous solution is 52 minutes (Walters et al, Jr Pharmac Sci 83 (1994) 758) which in the case of an extended therapy would require for the patient an unacceptable frequency of administration.
Similarly, the subcutaneous injection of N-0923 in an aqueous solution (5% dextrose) was only effective for the very short time of 60-70 minutes (Belluzzi, Movement Disorders, 9.2 (1994) 147).
This leaves a need for non-oral forms of N-0923 medication so formulated as to significantly reduce the number of necessary therapeutic applications.
That is why in recent times transdermal systems have been developed. WO 94/07468 describes a diphasic matrix that may contain N-0923 as the active agent. WO 99/49852 discloses a monophasic matrix for the transdermal administration of N-0923.
Transdermal systems, however, are not suitable for all patients, and they pose a number of inherent problems. For example, numerous patients develop allergic reactions to such substances in the pads as adhesives, penetration enhancers and polymers.
Then, too, the acceptance of medicinal pads varies extensively as a function of national traditions and ethnocultural peculiarities.
Finally, with transdermal systems it is only marginally possible to select individualized dosages.
It is therefore the objective of this invention to introduce an alternative pharmaceutical formulation that includes a possible minimum of components while avoiding the above-described drawbacks of both transdermal and oral administration such as poor bioavailability, high frequency of administration, an immunogenic potential, possible toxicity and inadequately individualizable dosaging.
According to the invention, this objective has been achieved by the first-of-its-kind pharmaceutical formulation of the active agent N-0923 in depot form that is capable of continuously releasing the N-0923 over a duration of at least 24 hours.
In one preferred form of implementation the pharmaceutical formulation is an oily suspension containing the N-0923 in its solid phase.
In another preferred form of implementation, N-0923 is contained in an anhydrous formulation in the form of a crystalline salt which, when applied to a mammal, results in a continuous plasma level of 0.2-10 ng N-0923/ml blood over at least 24 hours.
Surprisingly, it is possible with this very simply structured formulation according to the invention to attain a therapeutically relevant N-0923 plasma level for as long as 48 hours. Moreover, the composition according to the invention can be produced easily and cost-effectively, it is biodegradable, nontoxic, biocompatible and well-tolerated.
As a particularly desirable feature, the pharmaceutical composition according to the invention contains but few, well-defined and well-tolerated additives.
Individualized quantification of the application volume or of the active-agent concentration, makes it very easy to adapt the dosage to the specific needs, symptoms and condition of the patient concerned.
The therapeutic compositions according to the invention thus lend themselves superbly to the treatment of diseases related to metabolic dopamine disorders such as Parkinson's disease or Restless Leg. Such treatment can be in the form of monotherapy but also in combination with other active agents or biocatalysts.
It was also found, rather unexpectedly, that when heated during the thermal sterilization process, N-0923 remains stable provided it is contained in the pharmaceutical compositions according to the invention in its solid phase. By contrast, dissolved N-0923 when heat-sterilized undergoes substantial thermal decomposition.